A tumor is an abnormal benign or malignant growth of cells or tissue that arises from uncontrolled cellular proliferation. A malignant tumor is a one that spreads from its site of origin, and is also art-known as a cancer. Thus, tumors and cancers are a family of diseases sharing the common property of uncontrolled or inappropriate cell growth. Broadly, malignant tumors are either blood derived tumors, such as leukemia, or solid tumors. Blood derived malignant tumors generally circulate in the blood, but solid malignant tumors spread throughout the body from a primary tumor. The distributed tumor cells then have the potential to develop into multiple secondary tumors, in a process of metastasis. In order for a solid tumor to undergo such a metastatic spread, solid tumor cells must escape from the primary or original tumor, enter the blood stream or lymphatic system, and from there invade the tissue of other organs, where they multiply and form new tumors. Metastasis is a complex multi-step process that involves changes in tumor cell adhesion and motility, secretion of proteolytic enzymes, chemoattractants, and proteoglycans and other factors. In addition, angiogeniesis, or the formation of new blood vessels, is also a vital step in the metastatic process (Folkman, 1995, Nature Medicine 1:27-31).
The immune system has also been shown to inhibit the metastasis of such malignant tumor cells, and it has been reported that adenosine, in turn, may inhibit such immune protective reactions. For example, Loshkin et al., (2006, Cancer Res. 66: 7758-7765) report that adenosine inhibits activation and cytokine production in killer T cells. Adenosine negatively impacts other immune function, including both cellular elements and inflammatory functions (see, e.g., the reviews by Spychala, 2000, Pharmacology & Therapeutics 87: 161-173 and by Sitkovesky et al., 2005 Nature Reviews Immunology 5: 713-721). Sitkovesky et al., in WO 03/050241, published Jun. 19, 2003, also described methods for increasing an immune response to an antigen and for treating tumors, by administering an adenosine receptor antagonist, that can include adenosine deaminase.
It has also been shown that adenosine promotes tumor cell migration and angiogenesis (Barcz et al., 2000, Oncol. Rep. 7(6): 1285-91; Adair, 2005 Am J Physiol Regul Integr Comp Physiol 289: R283-R296) and that adenosine stimulates the proliferation of colon cancer cells (Mujoomdar et al. 2003, Biochemical Pharmacology 66 1737-1747). It has also been reported by Asmar et al., 1966, Proc. Am. Assoc. Cancer Res. (Abstract No. 73) that the growth of certain tumor cells was inhibited, by injection of ADA, by over 50% in a mouse ascites model. These were lymphatic leukemias L1210 and L4946, lymphosarcoma 6C3HED, mammary adenocarcinoma TA3, and Ehrlich carcinoma E2. In the same Abstract, an adenocarcinoma 755 was reported to be twice as resistant to and a sarcoma 180 was completely resistant to the effect. WO03050241 A2 describes the effects of an inhibitor of adenosine receptors on B16 melanoma cells. While WO03050241A2 mentions ADA as an inhibitor of adenosine, there is no specific description for applying ADA to the treatment of specific cancers, and particularly ovarian cancer and prostate cancer.
Thus, it seems that for some tumors, the presence of adenosine provides a “go” signal for tumor proliferation and for tumor angiogeniesis, and a “stop” signal for the killer T cells which would normally kill these tumors.
In contrast to the above-discussed findings, Lind, et al. (U.S. Pat. No. 6,579,857) have reported that adenosine, in combination with an inhibitor of the enzyme adenosine deaminase, and/or in combination with an anticancer agent such as coformycin, is useful in a method for potentiating cell death in neoplastic cells of epithelial origin. Thus, this reference suggests that the role of adenosine in cancer is more complex and unsettled.
As noted above, an agent for reducing endogenous adenosine levels is the enzyme adenosine deaminase. Adenosine deaminase (“ADA”), designated as EC 3.5.4.4, is an important enzyme of the purine salvage pathway. ADA converts either adenosine or deoxyadenosine, in the presence of water, into inosine or deoxyinosine and ammonia. It is known that individuals who harbor deleterious mutations in the ADA gene can develop varying degrees of an immunodeficiency disorder, from mild to severe, i.e. severe combined immunodeficiency disorder (“SCID”). SCID has been confirmed to result from the toxic accumulation of the enzyme substrates, adenosine and deoxyadenosine, in immature lymphoid cells. The onset of the disorder can range from early childhood to adults, depending on the mutations inherited. Deficiencies of ADA are one of the leading causes of SCID, in children, and is one of the leading targets for gene therapy approaches (R. Parkman et al., 2000, Gene therapy for adenosine deaminase deficiency, Ann. Rev. Med., 51:33-47).
Previously, ADA has been commercially isolated from bovine sources and employed in treating a number of disorders, including SCID, in the form of a bovine ADA conjugated to polyethylene glycol (“PEG”) polymer. PEGylated ADA for medical use is commercially available from Enzon Pharmaceuticals, Inc. as ADAGEN®, PEGylated ADA. The conjugation of a PEG moiety to ADA allows the enzyme to achieve its full therapeutic effect by increasing the circulating life and rendering the ADA substantially non-antigenic, in order to minimize the potential for immunogenic reactions. It is also possible to produce recombinant human or bovine ADA enzymes for use in a conjugated form, as described by co-owned U.S. patent application Ser. No. 11/738,012, entitled “Stabilized Proteins”, and co-owned U.S. application Ser. No. 12/105,913, entitled “Stable Recombinant Adenosine Deaminase”, filed on even date herewith and claiming the benefit of priority from U.S. Patent Application Ser. No. 60/913,009, and both incorporated by reference herein in their entireties.
Thus, there is a longstanding need in the art for new and improved methods of treating or inhibiting the growth, spread and development of cancers.